Peroxisome proliferator-activated receptor-gamma (PPARgamma) and -delta (PPARdelta) are major regulators of fat metabolism. They belong to the nuclear receptor super-family of ligand activated transcription factors. Highly selective PPARgamma and PPARdelta ligands are promising drugs or drug candidates for the treatment of type 2 diabetes and obesity. However, the molecular mechanism by which these ligands act as anti-diabetes and/or anti-obesity agents has largely remained unclear. The tripartite nature of the nuclear receptor biology suggests that the biological effect of a ligand is determined by the combinatorial collaboration among these three parts: ligand, nuclear receptor, and cofactors (coactivators or corepressors) recruited by ligand-bound nuclear receptor on the target gene promoters. To understand the molecular mechanism by which ligand-activated PPARgamma and PPARdelta transcriptionally regulate fat metabolism, three projects using proteomic and genomic approaches have been initiated in the laboratory in collaboration with Dr. Markus Kalkum of the Beckman Research Institute of the City of Hope. I: Proteomic isolation and characterization of transcription cofactors for PPARgamma. II: Proteomic isolation and characterization of transcription cofactors for PPARdelta. III: Identification and characterization of PPARgamma and PPARdelta target genes.